Materials and methods for protecting against neuromas

ABSTRACT

The subject invention provides devices and methods for alleviating discomfort associated with neuroma formation. The devices and methods of the invention effectively use the body&#39;s natural response of reconstructing implanted biomaterials to minimize the size of, isolate, and protect a neuroma. In preferred embodiments, the subject device is a cylindrical cap, wherein the internal chamber of the cylindrical cap physically partitions the nerve to enable an arrangement of nerve fibers (as opposed to haphazardly arranged nerve fibers often produced in neuromas). Tabs arranged on the outside of the cap can be used to manipulate the cap into place on a nerve. The open end can also be configured with flaps that can be used to widen the open end for easier insertion of the nerve into the cap. In addition, the cap&#39;s material remodels into a tissue cushion after implantation, which protects the neuroma from being stimulated and inducing pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.14/036,405, filed Sep. 25, 2013, now U.S. Pat. No. 9,629,997, whichclaims the benefit of U.S. provisional application Ser. No. 61/705,251,filed Sep. 25, 2012, which are incorporated herein by reference in theirentirety.

BACKGROUND OF INVENTION

Neuromas develop as a part of a normal reparative process followingperipheral nerve injury. They are formed when nerve recovery towards thedistal nerve end or target organ fails and nerve fibers improperly andirregularly regenerate into the surrounding scar tissue. Neuromasconsist of a deranged architecture of tangled axons, Schwann cells,endoneurial cells, and perineurial cells in a dense collagenous matrixwith surrounding fibroblasts (Mackinnon S E et al. 1985. Alteration ofneuroma formation by manipulation of its microenvironment. PlastReconstr Surg. 76:345-53). The up-regulation of certain channels andreceptors during neuroma development can also cause abnormal sensitivityand spontaneous activity of injured axons (Curtin C and Carroll I. 2009.Cutaneous neuroma physiology and its relationship to chronic pain. J.Hand Surg Am. 34:1334-6). Haphazardly arranged nerve fibers are known toproduce abnormal activity that stimulates central neurons (Wall P D andGutnick M. 1974. Ongoing activity in peripheral nerves; physiology andpharmacology of impulses originating from neuroma. Exp Neurol.43:580-593). This ongoing abnormal activity can be enhanced bymechanical stimulation, for example, from the constantly rebuilding scarat the injury site (Nordin M et al. 1984. Ectopic sensory discharges andparesthesiae in patients with disorders of peripheral nerves, dorsalroots and dorsal columns. Pain. 20:231-245; Scadding J W. 1981.Development of ongoing activity, mechanosensitivity, and adrenalinesensitivity in severed peripheral nerve axons. Exp Neurol. 73:345-364).

Neuromas of the nerve stump are unavoidable consequences of nerve injurywhen the nerve is not, or cannot be, repaired and can result indebilitating pain. It has been estimated that approximately 30% ofneuromas become painful and problematic. This is particularly likely ifthe neuroma is present at or near the skin surface as physicalstimulation induces signaling in the nerve resulting in a sensation ofpain.

Neuroma prevention and attenuation strategies have used various methodsto limit neuroma size and protect the neuroma from external stimuli.Current prevention methods attempt to limit the size of the neuroma andso reduce or limit potential contact and “cross-talk” between axonswithin the injured nerve site and within the disorganized structure thatcharacterizes neuromas. Due to a variety of factors, current methods ofneuroma mitigation/prevention have an unacceptable level of efficacy.

While various methods have been used to prevent, minimize, or shieldneuromas, the current clinical “gold standard” for treating neuromas isto bury the nerve end (that will form the neuroma) into muscle or a holedrilled in bone. The surrounding tissue cushions and isolates theneuroma to inhibit stimulation and the resulting painful sensations.However this procedure can greatly complicate surgery, as significantadditional dissection of otherwise healthy tissue is required to emplacethe nerve stump. For these reasons, emplacement of the nerve stump isoften not performed in amputations (and many other nerve procedures).

Another method is to cut the nerve stump back to leave a segment orsleeve of overhanging epineurium. This overhang can be ligated to coverthe face of the nerve stump. Alternatively, a segment of epineurium canbe acquired from other nerve tissue or a corresponding nerve stump canbe cut back to create an epineurium sleeve that can be used to connectwith and cover the other nerve stump.

Yet another method that is commonly used is a suture ligation, where aloop of suture is placed around the end of the nerve and tightened. Thispressure is believed to mechanically block the exit of axons and causesthe terminal end to eventually form scar tissue over the site. Clinicaland pre-clinical evidence has shown, however, that this procedure cancause a painful neuroma to form behind the ligation. Furthermore, theligated nerve is generally not positioned to minimize mechanicalstimulation of the neuroma, since it is anticipated that the scar tissuewill provide sufficient protection to the nerve end.

Other methods include covering the nerve stump with a silicone or rubbertube; a vein, or a silicone rubber plug (i.e. a tube with a sealed end)have also been used. These devices and methods necessitate insertion ofthe nerve into the opening of the device, which can be difficult and canfurther damage the nerve end. These methods and devices also maintainthe neuroma as a single mass, whereby stimulation in one area creates acascade effect that can eventually encompass the entire neuroma mass.Thus, even minor stimulation of a neuroma can cause the entire neuromamass to react.

Unfortunately, current methods for addressing the formation of and paincaused by neuromas have not been generally successful and therefore arerarely utilized. The formation of neuromas at a severed nerve end can bedifficult to prevent. As such, methods and devices that can inhibit oralleviate the pain caused by neuromas can provide relief to patients.

BRIEF SUMMARY

The subject invention provides devices and methods for alleviatingdiscomfort associated with neuroma formation. Specifically, the subjectinvention provides biomedical devices and methods for neuroma sizelimitation and neuroma protection and isolation.

In preferred embodiments, the subject device is a cylindrical cap with asingle open end to be applied to nerves within a subject's body, whereinthe internal chamber of the cylindrical cap has separators or dividersthat can physically partition the nerve structures into distinct, and insome embodiments, separate channels to enable a more regulararrangement, rather than the haphazard arrangement often produced inneuromas. Preferably the device is sterile and has a single open end,such that the nerve end can be inserted into the internal chamberthrough the open end. There can be a hollow indentation or retainingcavity between the open end and the separators or dividers in which theterminal end of the nerve can be situated and secured. As the nervegrows, the axons and other structures will extend and grown into theseparate channels to limit contact between them.

In one embodiment, the partitioning of the internal chamber of the capis in the form of a spiral-shaped wall that forms a longitudinalspiraled channel with one edge facing the open end. As nerve tissuegrows, it can fill in the space between the spirals, so that the outernerve tissue is substantially separated, subdivided, or partiallysubdivided from inner nerve tissue. In an alternative embodiment, theinternal chamber is partitioned with at least one panel, directedlongitudinally with the internal chamber, such that a portion of theinternal chamber, opposite to the single open end, is divided into twoor more distinct and separate channels. The division of the neuromatissue into separate or subdivided channels, to form smaller,disconnected, neuroma masses, can mitigate the cascade effect causedwhen one area of the neuroma is stimulated and the effect is feltthrough the entire tissue mass. The dimensions of the cylindrical capcan be about 1 mm to about 25 mm in diameter and about 1 mm to about 100mm in length.

In addition, the material of the cylindrical cap can remodel into atissue cushion after implantation, thereby enveloping and furtherisolating the new neuronal growth, which protects the neuroma from beingstimulated and inhibits pain. Remodeling can include, but is not limitedto, expansion or enlargement of the material, reshaping of the material,incorporation of the material around nerve tissue, and other changesthat can affect the size and shape of the material. Preferably, afterthe device is implanted, it will remodel into the surrounding tissue toprotect the forming neuroma and the sections of smaller, disconnectedneuromas mass. In one embodiment, the material of the cap is abiomaterial that can remodel to generate a volume of protectiveconnective tissue around a neuroma (rather than the current use of abiomaterial to contain a neuroma volumetrically). In a preferredembodiment, the material of the cap is a membrane biomaterial, such as,for example, small intestine submucosa (SIS), amnion, dermis, ordecellularized fascia.

In one embodiment of a method of use, a device is provided that containsan internal chamber with a retaining cavity at or near the open end toallow insertion of the nerve stump through the open end, so that it isnear or abuts against the divided, or separate, channels facing the openend. A dense layer of biomaterial on the exterior surface can operate tomechanically isolate the neuroma and prevent axons from escaping theinternal chamber of the device. The internal chamber contain partitionsor dividers of biomaterial to subdivide the neuroma mass 13 intosmaller, disconnected neuroma masses 17 as it grows that will form fromthe nerve stump.

Insertion of a terminal nerve end into the internal channel can bedifficult. A terminal nerve end is one that has been cut or transectedleaving exposed axons and other internal nerve structures. Usually,either the outside of the cap and/or the epineurium around the nerve areheld with a forceps so the nerve can be moved through the open end.Excessive pressure applied to the nerve can damage internal axons andstructures. Likewise, excess force applied around the cap can distortthe shape or the open end, inhibiting insertion of the nerve end. Anopen end in the cap that is too large can allow the neuroma to escapeand grow outside the cap. If the open end is made smaller, the nerve canbe damaged if forced into the open end.

In one embodiment, to facilitate insertion of a terminal nerve end, acap can have one or more tabs arranged on and around the externalsurface 16 of the cap. In an alternative embodiment, a tab can bearranged at or near the open end. The tabs can be used to grasp the capand manipulate it around the terminal nerve end. Grasping the tabsrather than the exterior surface can help to maintain the shape of thecap, in particular the open end.

The open end leading into a retaining cavity in which the terminal nerveend can be secured can also be made temporarily larger or moreaccessible, so that the terminal nerve end can be more easily and gentlyplaced therein. In one embodiment, there is a slit in the cap that isintegral with and perpendicular to the opening, such that the openingcan be temporarily widened. In another embodiment, the retaining cavityhas one or more wings or flaps that allow it to be partially spreadopen. This can widen the open end sufficiently that a terminal nerve endcan be placed or set down within the retaining cavity, making it easierto see how it is placed relative to the dividers. The wings or flaps canthen be wrapped over and around the nerve end and secured to hold thenerve in place and inhibit escape of neuronal tissue growth.

The combination of limiting the growth and size of a neuroma massthrough physical partitioning of the neuromas mass into smaller,disconnected sections along with the creation of a connective tissuecushion is unique. This novel combination of features and designeffectively uses the natural response of reconstructing implantedbiomaterials to minimize the size, isolate, and protect the neuroma.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B and 1C show a schematic presentation of consecutive stepsof various current nerve stump capping methods: Step 1—nervetransection; Step 2—nerve stump preparation (A and B, nerve sheath mustbe slid off, then a piece of the nerve is removed to prepare asleeve-like fragment of epineurium; C, cap can be formed of anyautologous tissue, sutured to the epineurium); Step 3—the end ofepineurium can be tied up or sutured. Lewin-Kowalik J. et al. (2006)Prevention and Management of Painful Neuroma. Neural Med Chir (Tokyo),46:62-68.

FIGS. 2A, 2B and 2C show perspective views (2A and 2C) of twoembodiments of the invention and a side view (2B) of an embodiment ofthe device of the subject invention.

FIGS. 3A and 3B show a side cut-away view (FIG. 3A) of and top view ofthe proximal end (FIG. 3B) of the embodiment.

FIG. 4A is a schematic drawing showing an untreated neuroma.

FIG. 4B is a schematic drawing showing a neuroma treated using anembodiment of a device of the subject invention.

FIG. 5A is a schematic drawing showing a perspective view of anotherembodiment of the device of the invention.

FIG. 5B is a view illustrating a press-forming process executed by thepress-forming apparatus to manufacture an embodiment of the device shownin FIG. 5A.

FIGS. 6A, 6B, 6C, 6D, and 6E illustrate embodiments of a cap, accordingto the subject invention, configured with a tab by which the cap can bemanipulated and an internal panel that subdivides a portion of thedistal end of the internal chamber into separate channels. FIG. 6A is aproximal end perspective view of an embodiment. FIG. 6B is top side,proximal end perspective view of the embodiment. FIG. 6C is a right sideelevation view of the embodiment. FIG. 6D is a top side plan view of theembodiment. FIG. 6E is a left side perspective view of an alternativeembodiment of a cap with a tab extending from the edge of the open end.

FIGS. 7A, 7B, 7C and 7D illustrate an embodiment of a cap, according tothe subject invention, configured with multiple tabs by which the capcan be manipulated and also shows several internal panels that subdividea portion of the distal end of the internal chamber into multipleseparate channels. The example shown in FIGS. 7A and 7B has a tab at thedistal end and two tabs on the right and left sides. Also shown in thisexample are three perpendicularly placed panels within the internalchamber. FIGS. 7C and 7D illustrate an alternative embodiment where morethan one panel is arranged parallel with each other in the internalcavity.

FIGS. 8A, 8B, 8C, 8D, and 8E illustrate embodiments of a cap, accordingto the subject invention, where the open end is configured with one ormore flaps that partially spread or widen the open end to allow aterminal nerve end to be more easily placed within the retaining cavity.FIG. 8A shows an embodiment with one flap and FIG. 8B shows anembodiment with two flaps. FIG. 8C illustrates how distal edge of theflaps can open directly onto the separate channels. FIG. 8D illustratesan alternative embodiment where the distal edges of the flaps openproximal to the separate channels. FIG. 8E shows a non-limiting exampleof a cap with a slit at the open end, such that there is are tri-cornerflaps that can be used to temporarily widen the open end.

DETAILED DISCLOSURE

The subject invention provides devices and methods for alleviatingdiscomfort associated with neuromas. More specifically, the subjectinvention pertains to devices and methods for limiting neuroma size andphysically surrounding the neuroma to inhibit stimulation that elicitsneuropathic pain. In certain embodiments, the subject invention isdirected to a tissue-engineered scaffold that provides: a barrier thatlimits the size of a neuroma, dividers that subdivide the neuroma volumeor mass into smaller, disconnected neuromas masses to reduce axonalcross-talk or the “cascade effect,” and mechanical isolation of theneuroma to inhibit stimulation.

A device of the subject invention is designed to form a protective,connective tissue covering or cap surrounding the terminal nerve end 29,thereby surrounding any resulting neuroma formation. Within the volumecreated by the barrier, sub-dividing the neuroma volume as it forms canlimit the amount of interaction between axons, thereby limitingsignaling cascades being triggered inside the neuroma that can beinterpreted as pain. By providing mechanical isolation of the neuromavolume, the subject device limits stimulation of the neuroma. Theability of the material of the subject device to remodel into a nativetissue cushion is another advantageous feature when combined with thephysical partitioning of the neuroma.

Current methods for limiting the size and stimulation of a neuroma areshown in FIGS. 1A-1C. The methods include dissecting or cutting theterminal end to form a flap of epineurium that can be folded over theterminal nerve end 29, as shown in the first column of FIGS. 1A-1C. Thenerve can also be dissected or cut back to form a sleeve of epineuriumthat can be ligated over the terminal nerve end, as seen in the middlecolumn in FIGS. 1A-1C. A patch epineurium can be obtained from anotherlocation and attached to the terminal nerve end, as shown in the lastcolumn in FIGS. 1A-1C.

The subject invention provides the benefits of an epineural flap (orligation) to limit neuroma size and the advantages of isolating a nerveend by emplacement in another tissue combined in a single device. Thisdevice isolates and protects the neuroma, thereby inhibiting painfulsensations without the need for any repositioning of the nerve.Advantageously, the device can be secured to the stump of the nerveprior to formation of a neuroma and as the neuroma forms the material ofthe device can remodel into a tissue cushion 55 and become integratedinto the surrounding host tissues, which effectively isolates theneuroma from undesirable contact and stimulation.

FIGS. 2A-8B illustrate embodiments of the invention. In one embodiment,illustrated in FIG. 2, the cap 10 of the subject invention has anexternal body 15 that comprises a proximal end 20 and a distal end 25.

It can be seen in FIG. 2 that one embodiment of the external body 15 ofthe cap 10 is cylindrical in shape. However, the shape of the externalbody 15 of the cap 10 can vary depending upon the type, diameter andlocation of a nerve stump, as well as other factors known to those withskill in the art. For example, the circumferential shape of the externalbody can be variable and be, by way of non-limiting examples, an ovoid,a circle, a square, a rectangle, a triangle, or any other polygonalshape. In an exemplified embodiment, the circumferential shape of theexternal body is generally a circle.

The dimensions of the external body can vary depending on the type,diameter and location of a nerve stump on which it will be used, as wellas other factors known to those skilled in the art. In one embodiment,the external body of the device has dimensions of approximately 1 mm toapproximately 100 mm in diameter and is approximately 1 mm toapproximately 500 mm in length, between the proximal end 20 and thedistal end 25. In a particular embodiment, the external body of thedevice will be less than 100 mm in diameter and less than 500 mm inlength. In a specific embodiment, the diameter of the external body isbetween approximately 1 mm and approximately 25 mm and the length of theexternal body, between the proximal end and the distal end of the cap,is between approximately 1 mm and approximately 100 mm.

In one embodiment, the diameter of the distal end 25 of the externalbody 15 can be narrower than the diameter of the proximal end 20, asseen, for example, in FIGS. 2 and 3. This can give the cap a bullet orconical shape. In a particular embodiment, shown for example in FIGS.2A-2C, the distal end 25 of the external body is cone-shaped. In analternative embodiment, shown for example in FIGS. 6A-6E and FIGS.7A-7B, the diameter of the distal end and the proximal end are the sameor substantially the same, such that the distal end of the cap is flat,giving the cap a cylinder or barrel shape.

Ideally, the external body 15 of the cap 10 has no openings other thanthe open end 18 at the proximal end 20 of the cap through which a nervecan be inserted or placed. In one embodiment, for example, as shown inFIG. 3, the proximal end 20 is open and the distal end 25 of theexternal body 15 is closed off entirely so that the external body formsa cap 10. FIG. 3 also illustrates an embodiment in which an internalchamber 35 is provided in the external body 15. In certain embodiments,the interior surface 22 of the closed off 30 portion of external body 15can be in the form of a bevel 40, as shown in FIG. 3A. Alternatively, aclosed off portion can be substantially flat, as shown in FIGS. 6C and7A. In yet another alternative, the closed off portion or closed end 30can be conical, such as shown, for example, in FIGS. 2A and 6E.

An external body without excess openings can inhibit axon growth fromextending outside the cap. The open end 18 of the cap can provide theonly access into the internal chamber. Fitting a terminal nerve end 29through the open end of a cap can be challenging and can potentiallydamage the nerve. If a cap with a larger diameter is selected, it can beeasier to insert the terminal nerve end, but may result is excess spacearound the nerve perimeter. If not properly closed off, the openingsaround the nerve can allow axons to escape.

The use of flaps 90 around the open end 18 can provide a temporaryenlargement of the open end, making nerve placement into the internalchamber easier, while the flap can be wrapped around and sutured toprovide for a close fit around the terminal nerve end. The enlargementof the open end allows a terminal nerve end to be moved through a slot92 formed in the open end. FIGS. 8A and 8E illustrate non-limitingexamples of a cap having an open end 18 with one or more flaps. Ideally,the slot provided by one or more flaps is large enough to allow aterminal nerve end to pass through the slot, with minimal compression ofthe nerve tissue, so as to minimize the number of sutures necessary toclose the flap and the slot.

In one embodiment, there is a single flap, as shown in FIG. 8A. Thesingle flap can provide a slot of between approximately 25% toapproximately 75% of the diameter of an opening 18. In a more particularembodiment, there is a single flap that provides a slot of betweenapproximately 35% to approximately 65% of the diameter of the opening.In a specific embodiment, there is a single flap that provides a slot ofbetween approximately 45% to approximately 55% of the diameter of theopening. In a specific embodiment, there is a single flap that providesa slot of approximately 50% of the diameter of the opening.

In an alternative embodiment, there are two flaps, as shown in FIG. 8B.The dual flaps can open in opposite directions. The dual flaps canprovide a slot of between approximately 25% to approximately 75% of thediameter of an opening 18. In a more particular embodiment, there is asingle flap that provides a slot of between approximately 35% toapproximately 65% of the diameter of the opening. In a specificembodiment, there is a single flap that provides a slot of betweenapproximately 45% to approximately 55% of the diameter of the opening.In a specific embodiment, there is a single flap that provides a slot ofapproximately 50% of the diameter of the opening.

In an alternative embodiment, there is a slit 98 in the proximal end 20of the cap that is integral with opening 18 and that advances towardsthe distal end 25 to form a flap with three corners part-way along theexternal body 15 of the cap. FIG. 8E illustrates a non-limiting exampleof a three-corner flap.

The nerve tissue in a neuroma mass 13 grows in a random, haphazardfashion and the axons in one section of a neuroma can be in contact withother surrounding axons. This creates the disadvantageous effect of theneuroma acting as one, open nerve end. As a result, stimulation of aneuroma in one area can trigger a cascade effect wherein the signalreceived by axons in one area, because of contact, will trigger signalsin nearby axons. Each step in the cascade can amplify the initial signaluntil finally most or all of the axons in the neuroma are “fired.” Thismassive signal cascade can also amplify pain. By isolating or separatingareas of the neuroma from other areas of the neuroma, this cascadeeffect can be minimized, thereby limiting the amount of pain caused bystimulation of the neuroma.

In one embodiment, the internal chamber 35 can be configured with one ormore dividers 70 that subdivide at least a portion of the internalchamber into two or more separate channels 36 into which the neuromamass 13 can grow and become portioned into smaller, disconnected neuromamasses. This separation of the neuroma mass into the different channelscreates a physical barrier between the axons of the smaller,disconnected portions in the different separate channels, therebylimiting the scope of a cascade effect. The dividers 70 used in aninternal chamber can be configured in a myriad of ways to createdifferent sizes and shapes of separate chambers. Likewise, the dividerscan be individual or unconnected or they can be joined together.Variations in the configurations of the dividers that separate a neuromamass into smaller, disconnected masses 17 or portions with differentchannels are within the scope of this invention.

A nerve end can be positioned within the cap 10 so that the neuronalgrowth is directed towards the closed end 30 and the separate chambers.It can be beneficial if there is some overlap between the external bodyand the epineurium, so as to provide space or distance between the endof the nerve and the open end when the terminal nerve end 29 is securedin the cap. This can be achieved by having the dividers 70 terminatesome distance from the open end, thereby forming a retaining cavity 60between the open end 18 and a divider. FIGS. 6A, 6C, 7A, and 7Dillustrate non-limiting examples of dividers that are shorter than thelength, between the distal end and the proximal end of the cap, of theexternal body 15. The termination of the dividers before the open endforms an undivided retaining cavity in which the terminal nerve end canbe disposed. The subsequently forming neuroma will be directed towardsthe separate channels and divided into separate, smaller, disconnectedportions or volumes as it grows into the separate channels.

In one embodiment, a divider is shorter than length of the internalchamber, such that between approximately 25% to approximately 75% of theinternal chamber is divided into separate channels. In a more particularembodiment, a divider is shorter than the length of the internalchamber, such that between approximately 40% and 60% of the internalchamber is divided into separate channels. In a specific embodiment, adivider is shorter than the length of the internal chamber, such thatapproximately 50% of the internal chamber is subdivided into separatechambers.

According to one embodiment of the invention, the external body 15 canhave an internal chamber 35 that includes spiral partitions 45.Advantageously, the spiral partitions enable subdivision and arrangementof axons from the nerve stump. In certain related embodiments, theinternal chamber of the external body comprises a tightly packed spiralof a solid sheet of biomaterial. Preferably, where the internal chamberof the external body comprises a tightly packed spiral of a solid sheetof biomaterial, there are no voids present that could lead to axonalescape from the device.

In an alternative embodiment, the internal chamber can be subdivided byseparate concentric tubes 46, such as shown, for example, in FIG. 2C.The concentric tubes 46 can also partition or subdivide the internalchamber, enabling the formation of smaller, disconnected neuromas masses17. In another embodiment, the divider 70 is a panel that extends acrossand attaches to the internal surface 22 of the internal chamber 35. Thepanel divider can extend from the closed portion 30 at distal end 25 andtowards the open end 18 proximal end 20 thereby dividing the closed offportion 30 of the internal chamber in a longitudinal direction 28 intotwo separate channels 36. In a further embodiment, the panel dividerextends partially through the internal chamber, such that a portion ofthe internal chamber is subdivided and another portion, nearer theproximal end, remains undivided. FIGS. 6A-6D illustrate a non-limitingexample of this embodiment. In a further embodiment, there can be morethan one panels so that the internal chamber is divided into more thantwo separate channels. FIGS. 7A and 7B illustrate non-limiting examplesof 2 and 3 panels arranged perpendicularly, dividing the internalchamber into four quadrants. FIGS. 7C and 7D illustrate anothernon-limiting example of multiple panels arranged parallel within theinternal chamber, dividing the internal chamber into similar parallel,separate channels. Other arrangements of panels that form differentconfigurations of separate channels are within the scope of thisinvention.

In one embodiment, a panel extends in a longitudinal direction 28between approximately ¼ to approximately ¾ of the length, between theproximal end 20 and the distal end 25 of the internal chamber. In a morespecific embodiment, a panel extends in a longitudinal direction betweenapproximately ⅖ to approximately ⅗ of the length of the internalchamber. In a specific embodiment, a panel extends approximately ½ ofthe length of the internal chamber.

The flaps 90, mentioned above, can provide a slot 92 that allows theterminal nerve end 29 to be placed in close proximity to the dividers70. In one embodiment, the flaps have a rear edge 96 that allows theflap to open onto the dividers, so that the slot is directly open to thedividers, allowing a terminal nerve end to be placed against thedividers, which is shown, for example, in FIG. 8C. In anotherembodiment, the flaps have a rear edge 96 that is proximal to thedividers, such that the flap opens more proximal 20 to the dividers,providing for at least a small retaining cavity 60 between the rear edgeor the slot and the dividers, such as shown, for example, in FIG. 8D.

In an alternative embodiment, the flap is formed by a slit 98 in theexternal body of the cap, extending from the opening towards the distalend. FIG. 8E illustrates a non-limiting example of a flap fanned by asingle slit 98 in the external body. The slit can extend part-waytowards the distal end, such that it terminates at the dividers 70, suchthat the slot 92 opens onto the dividers. Alternatively, the slit 98 canterminate proximal to the dividers, such that the slot 92 opens moreproximal or a distance in front of to the dividers, providing for atleast small retaining cavity 60 between the dividers and the end of thedistal end of the slit.

In one embodiment, as illustrated in FIG. 4B, the internal chamber 35 isan unchambered or undivided layer of biomaterial 50. The biomaterialpreferably isolates the neuroma and prevents axons from escaping theexternal body 15 of the device. FIG. 4A is a schematic drawing showingan untreated neuroma.

Both natural and synthetic biomaterials can be used to manufacture a capand components thereof of the subject invention. In certain embodiments,the biomaterial is a homogenous material. Examples of biomaterials foruse in manufacturing the subject invention include, but are not limitedto, high density polyethylene (HDPE), polyethylene glycol (PEG)hydrogel, purified proteins from human or animal sources (e.g., membraneof purified collagen or fibrin), and decellularized tissue constructs(e.g., demineralized bone, amnion, SIS, dermis, or fascia). An HDPE orPEG device can comprise or consist of a cylinder of porous HDPE or PEGsurrounded by a layer of non-porous HDPE or PEG. Biomaterials that canform a fluid material, such as soluble purified collagen or particulateSIS and dermis, can be directly cast to form the device without amembrane as an intermediate.

In certain embodiments, the external body 15 of the device can be madeby rolling a sheet of biomaterial to form spiral partitions. Where theexternal body of the device is a “roll” of spiral partitions, the layersof the roll separate slightly to allow nerve regeneration to proceed ashort distance into the device before encountering, and being stoppedby, infiltrating non-nerve tissue (i.e., the rolled version haslongitudinal pores or characteristics). In specific related embodiments,layers of the rolled biomaterial are situated such that a spiral channelis present on the face of the device facing the nerve stump, while thedevice face external to the nerve stump is solid.

In other embodiments, the external body of the device can be made of aporous biomaterial. In yet other embodiments, the body includes a hollowcentral cavity to facilitate insertion of a nerve stump. In certainother embodiments, a body is provided with a hollow cavity whereinlayers of biomaterial scaffolding fill a portion of the hollow cavity tocreate a laminar or multi-laminar construct 60 (see FIG. 2C).

In an alternate embodiment, as illustrated in FIG. 5A, the external body15 of the device resembles a test tube, where the body is made of a thinlayer of biomaterial (either a single layer or multiple layers) andthere is a hollow central cavity 55 to facilitate insertion of a nervestump.

Illustrated in FIG. 5B is a method for producing the embodiment of thedevice shown in FIG. 5A. FIG. 5B illustrates a press formation apparatus100 for manufacturing the device of FIG. 5A. As shown in FIG. 5A, a thinlayer of biomaterial 105 (formed from either a single layer or multiplelayers of biomaterial) is mounted on a receiving portion 115 of thepress formation apparatus 100. The receiving portion 115 has an opening120 for receiving a punch 125, where the shape of the opening 120corresponds with that of the punch 125. The receiving portion 115 andthe punch 125 can be manufactured by die molding. Preferably, the punch125 is rod shaped; however, other shapes known to the skilled artisancan be used for the opening of the receiving portion and the punch.

The thin layer of biomaterial 105 is arranged over the opening 120 ofthe receiving portion 115. Once the biomaterial 105 is positioned, thepunch 125 is then driven downward and received in the opening 120. Inthis way, the body 15 of the device is formed.

In further embodiments, a cylindrical body having a hollow interior withopen ends is provided. The distal end of the body may be “crimped”during the manufacturing process to present a more solid biomaterial asa barrier to axonal escape from the device. An example is the use of acrimped mold during vacuum pressing of a rolled cylinder, such that oneend is of a smaller diameter.

In a preferred embodiment, the body of the subject device comprises acylinder of SIS. A hollow cavity is provided at the proximal end toallow insertion of a nerve stump. A deep spiral partition is present inthe body to subdivide the neuroma that will form from the nerve stump,and a dense layer of biomaterial is provided on the entire exteriorsurface to mechanically isolate the neuroma and prevents axons fromescaping the device.

In a method of use, a nerve stump is secured in the internal chamber 35by means of a suture, staple, clip, or surgical adhesive or sealant.After implantation, the cap is remodeled into the body's own tissue andprovides a tissue cushion 55 for the neuroma. As host cells infiltratethe biomaterial, it is converted into a form of connective tissue. Axonsand Schwann cells will also infiltrate from the stump. As fibroblasts(and other cells supporting remodeling into a connective tissue) 1)migrate and proliferate faster than Schwann cells/axons and 2)infiltrate from multiple sides and 3) axonal regeneration stops when itencounters other tissues (such as muscle, connective tissue layers,etc); the device will result in a layer of connective tissue surroundinga small neuroma in a vascularized tissue capsule. This capsule providesthe desired isolation and protection.

It can be beneficial for the nerve end to be fully encapsulated withinthe cap, so that when the nerve begins to grow and form a neuroma, allneuronal growth is contained within the cap and, preferably, directedtowards the separate channels at the closed end 30. Manipulation of aterminal nerve end 29 into a cap can be difficult. Nerve tissue isusually soft and susceptible to damage if too much force is applied.Typically, the cap is manipulated onto the terminal nerve end. The capcan be grasped or encircled by various instruments to manipulate it ontothe terminal nerve end. This can distort the shape of the external bodyand make it difficult to manipulate onto the terminal nerve end.

In one embodiment, the external body 15 is configured with one or moretabs 80 extending out from the external body. The tabs can providepoints for grasping the cap without contacting, or by making minimalcontact, with the external body. A tab can be any size or shape andthere can be more than one tab on an external body. Preferably, the sizeand shape of a tab provides opposing surfaces 82 for grasping with aforceps or any other instrument with pincers that can be squeezedtogether to grasp or hold small structures. A tab can also be used as aconnection point, wherein by the cap and a terminal nerve securedtherein can be attached to another structure in the body using a tab. Inone embodiment, a tab comprises the same or similar material as the cap.For example, a tab can be formed from the same biomaterial that the capis formed from, allowing the tab to be remodeled with the cap, asdescribed above. In an alternative embodiment, the tab comprises adifferent material than the cap. For example, a tab can comprise apolymer that dissolves or is absorbed by the body. After the tab hasbeen used to manipulate the cap into position, the tab can be left inplace on the cap. Alternatively, a tab can be removed from the cap, suchas by cutting with a scissors, blade, or compression sealing.

In one embodiment, a tab extends out from the closed end 30 of the cap10, such as shown, for example, in FIGS. 6B, 6C, and 6D. In theseFigures, the tab is shown traversing the full diameter of the closedend. This is not required and the width of the tab can be less than thediameter of the cap, which is not shown, but is understood by a personwith skill in the art.

In another embodiment, a tab can extend from the open end 18 of the cap10, such that it forms a lip or shelf around the edge 19 of the openend. FIG. 6E illustrates one example of a tab 80 extending from the edge19 of the open end 18. This type of tab can be used to pull the cap ontoa terminal nerve end. A tab extending from the edge of the open end canalso support a terminal nerve end placed thereon and other tabs on theexternal body 15 can be used to push the cap onto the terminal nerveend.

In addition to tabs that can be used to push or pull a cap onto aterminal nerve end 29, tabs can be located in and extend from otherareas of the cap and used to twist, turn, rotate, or otherwisemanipulate a cap 10 onto a terminal nerve end. In another embodiment, atleast one tab extends out from or away from a side of the external body.One example of this is shown in FIGS. 7A and 7B, where two tabs areshown extending out from each side of the external body.

Furthermore, tabs can be arranged in any of a myriad of orientations onthe external body. One embodiment, shown in FIG. 7B, has at least onetab arranged with an opposing surface parallel with, or approximatelyparallel with, the longitudinal direction 28 of the internal chamber 35.FIG. 6E shows an alternative embodiment where the tab is arranged withan opposing surface perpendicular, or approximately perpendicular, tothe longitudinal direction of the internal chamber. Tabs can also bearranged with an opposing surface, relative to the opening 18, at anoblique angle with the longitudinal direction of the internal chamber. Aperson with skill in the art will be able to determine, for one or moretabs, the appropriate location on the external body and orientation withrespect to the longitudinal direction of the internal chamber. Suchvariations are within the scope of this invention.

Neuroma formation occurs in approximately 30% of severed nerve ends.Without intervention, neuroma formation can form a randomly arrangedconglomeration of axons. This haphazard arrangement of axons makes theneuroma susceptible to a cascade effect when the neuroma is stimulated,where stimulation in one area radiates and intensifies through theentire neuroma mass, resulting in intense pain. The embodiments of thesubject invention can mitigate the effects of a cascade effect with capsthat can be attached to terminal nerve ends. The caps can aid inreducing the size of a neuroma and can provide channels for mechanicalseparation of a neuroma mass, thereby limiting the effect of stimulationof the neuroma. The caps of the subject invention also have externaltabs and flaps that can aid in fitting the cap over a terminal nerveend. The caps of the subject invention represent a significantimprovement in amelioration of the pain caused by neuromas.

Any reference in this specification to “one embodiment,” “anembodiment,” “example embodiment,” “further embodiment,” “alternativeembodiment,” etc., is for literary convenience.

The implication is that any particular feature, structure, orcharacteristic described in connection with such an embodiment isincluded in at least one embodiment of the invention. The appearance ofsuch phrases in various places in the specification does not necessarilyrefer to the same embodiment. In addition, any elements or limitationsof any invention or embodiment thereof disclosed herein can be combinedwith any and/or all other elements or limitations (individually or inany combination) or any other invention or embodiment thereof disclosedherein, and all such combinations are contemplated with the scope of theinvention without limitation thereto.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.

We claim:
 1. A sterile cap comprising: an external body having a distalend, a proximal end with a single opening, and an internal chamberbetween the distal end and the proximal end, where the external bodycomprises a biomaterial that remodels around a terminal nerve end toform a tissue cushion; at least one divider within the internal chamberthat subdivides at least a portion of the internal chamber, at thedistal end, where the at least one divider comprises a biomaterial thatremodels around the separate channels to form a tissue cushion betweenthe subdivided portions of the internal chamber; and a retaining cavitybetween the single opening at the proximal end and the at least onedivider.
 2. The cap according to claim 1, wherein the biomaterial isselected from the group consisting of: high density polyethylene (HDPE),polyethylene glycol (PEG) hydrogel, and purified proteins from human oranimal sources.
 3. The cap according to claim 1, wherein the biomaterialis selected from the group consisting of: small intestine submucosa(SIS), amnion, dermis, collagen and decellularized fascia.
 4. The capaccording to claim 1, wherein the at least one divider comprises atleast one of: a panel, a spiral shaped wall, and concentric tubes. 5.The cap according to claim 1, further comprising at least one tabextending from the external body.
 6. The cap according to claim 5,wherein the at least one tab extends from one or more of: a side of theexternal body, the distal end of the external body, and an edge of thesingle opening in the external body.
 7. The cap according to claim 1,further comprising at least one flap configured around the singleopening of the external body, where the at least one flap forms a slotto increase the size of the single opening and wherein the at least oneflap is adapted to be wrapped around the terminal nerve end to close theslot and reduce the size of the single opening around the terminal nerveend.
 8. The cap according to claim 7, wherein the at least one dividercomprises at least one of: a panel, a spiral shaped wall, and concentrictubes.
 9. The cap according to claim 7, further comprising at least onetab extending from the external body.
 10. The cap according to claim 9,wherein the at least one tab extends from one or more of: a side of theexternal body, the distal end of the external body, and an edge of thesingle opening in the external body.
 11. A method for covering andcontaining a neuroma mass at a terminal nerve end, comprising:positioning a cap, according to claim 1, at or near to a terminal nerveend prior to neuroma development, inserting the terminal nerve endthrough the single opening into the retaining cavity internal chamber,and securing the cap to the terminal nerve end to contain the neuromamass as it develops.
 12. A method for covering and containing a neuromamass at a terminal nerve end comprising: positioning a cap, according toclaim 5, at or near to a terminal nerve end prior to neuromadevelopment; inserting the terminal nerve end through the single openinginto the retaining cavity; and securing the cap to the terminal nerveend to contain the neuroma mass as it develops.
 13. The method of claim12, further comprising using the at least one tab to manipulate the caponto the terminal nerve end.
 14. The method of claim 12, furthercomprising attaching the at least one tab to other structures to securethe position of the cap and terminal nerve end therein.
 15. A method forcovering and containing a neuroma mass at a terminal nerve endcomprising: positioning a cap, according to claim 7, at or near to aterminal nerve end prior to neuroma development; inserting the terminalnerve end through the single opening into the retaining cavity; andsecuring the cap to the terminal nerve end to contain the neuroma massas it develops.
 16. The method of claim 15, further comprising spreadingthe flap before inserting the terminal nerve end into the retainingcavity.
 17. A method for covering and containing a neuroma mass at aterminal nerve end comprising: positioning a cap, according to claim 9,at or near to a terminal nerve end prior to neuroma development;spreading the flap; after spreading the flap, inserting the terminalnerve end into the retaining cavity; and securing the cap to theterminal nerve end to contain the neuroma mass as it develops.
 18. Themethod of claim 17, further comprising using the at least one tab tomanipulate the cap onto the terminal nerve end.
 19. The method of claim17, further comprising attaching the at least one tab to otherstructures to secure the position of the cap and terminal nerve endtherein.
 20. A method for preventing neuroma formation at a terminalnerve end comprising: positioning a cap, according to claim 1, at ornear to a terminal nerve end; inserting the terminal nerve end throughthe single opening into the retaining cavity; and securing the cap tothe terminal nerve end to contain the neuroma mass as it develops.
 21. Amethod for preventing neuroma formation at a terminal nerve endcomprising: positioning a cap, according to claim 5, at or near to aterminal nerve end; inserting the terminal nerve end through the singleopening into the retaining cavity; and securing the cap to the terminalnerve end.
 22. The method of claim 21, further comprising using the atleast one tab to manipulate the cap onto the terminal nerve end.
 23. Themethod of claim 21, further comprising attaching the at least one tab toother structures to secure the position of the cap and terminal nerveend therein.
 24. A method for preventing neuroma formation at a terminalnerve end comprising: positioning a cap, according to claim 7, at ornear to a terminal nerve end; inserting the terminal nerve end throughthe single opening into the retaining cavity; and securing the cap tothe terminal nerve end.
 25. The method of claim 24, further comprisingspreading the flap before inserting the terminal nerve end into theretaining cavity.
 26. A method for preventing neuroma formation at aterminal nerve end comprising: positioning a cap, according to claim 9,at or near to a terminal nerve end; spreading the flap; after spreadingthe flap, inserting the terminal nerve end into the retaining cavity andsecuring the cap to the terminal nerve end.
 27. The method of claim 26,further comprising using the at least one tab to manipulate the cap ontothe terminal nerve end.
 28. The method of claim 26, further comprisingattaching the at least one tab to other structures to secure theposition of the cap and terminal nerve end therein.
 29. A method forprotecting from external stimuli a neuroma mass at a terminal nerve endcomprising: positioning a cap, according to claim 1, at or near to aterminal nerve end; inserting the terminal nerve end through the singleopening into the retaining cavity; and securing the cap to the terminalnerve end to protect the neuroma mass as it develops.
 30. A method forprotecting from external stimuli a neuroma mass at a terminal nerve endcomprising: positioning a cap, according to claim 5, at or near to aterminal nerve end prior to neuroma development; inserting the terminalnerve end through the single opening into the retaining cavity; andsecuring the cap to the terminal nerve end to protect the neuroma massas it develops.
 31. The method of claim 30, further comprising using theat least one tab to manipulate the cap onto the terminal nerve end. 32.The method of claim 30, further comprising attaching the at least onetab to other structures to secure the position of the cap and terminalnerve end therein.
 33. A method for protecting from external stimuli aneuroma mass at a terminal nerve end comprising: positioning a cap,according to claim 7, at or near to a terminal nerve end prior toneuroma development; inserting the terminal nerve end through the singleopening into the retaining cavity; and securing the cap to the terminalnerve end to protect the neuroma mass as it develops.
 34. The method ofclaim 33, further comprising spreading the flap before inserting theterminal nerve end into the retaining cavity.
 35. A method forprotecting from external stimuli a neuroma mass at a terminal nerve endcomprising: positioning a cap, according to claim 9, at or near to aterminal nerve end prior to neuroma development; spreading the flap;after spreading the flap, inserting the terminal nerve end into theretaining cavity; and securing the cap to the terminal nerve end toprotect the neuroma mass as it develops.
 36. The method of claim 35,further comprising using the at least one tab to manipulate the cap ontothe terminal nerve end.
 37. The method of claim 35, further comprisingattaching the at least one tab to other structures to secure theposition of the cap and terminal nerve end therein.